Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat. Med. 14, 518-527

McGill Centre for Bioinformatics, 3775 University Street, McGill University, Québec H3A 2B4, Canada.
Nature medicine (Impact Factor: 27.36). 06/2008; 14(5):518-27. DOI: 10.1038/nm1764
Source: PubMed


Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor-derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node-negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.

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Available from: Greg Finak, Sep 30, 2015
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    • "RESULTS CDCP1 Is Overexpressed in Primary and Metastatic Human Breast Tumors, and CDCP1/HER2 Expression Correlates with Poor Patient Prognosis Recent studies have highlighted the role of CDCP1 in multiple human cancers (Wortmann et al., 2009). To investigate whether CDCP1 is overexpressed in human breast cancer, we first analyzed CDCP1 mRNA levels in three independent human breast cancer data sets (Finak, n = 59; TCGA, n = 450; and Curtis, n = 1,700) (Cancer Genome Atlas Network, 2012; Curtis et al., 2012; Finak et al., 2008), and found that in all three data sets CDCP1 was significantly overexpressed in human breast cancer compared with normal tissues (Figure 1A). To validate the protein level of CDCP1 in human breast cancer tissues, we first established CDCP1 immunohistochemistry (IHC) staining in a cell line expressing control or CDCP1 vectors (Figures S1A and S1B). "
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    ABSTRACT: Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of novel therapeutic interventions. Here, we show that CDCP1 and HER2 are frequently co-overexpressed in metastatic breast tumors and associated with poor patient prognosis. HER2 and CDCP1 co-overexpression leads to increased transformation ability, cell migration, and tumor formation in vivo, and enhanced HER2 activation and downstream signaling in different breast cancer cell lines. Mechanistically, we demonstrate that CDCP1 binds to HER2 through its intracellular domain, thereby increasing HER2 interaction with the non-receptor tyrosine kinase c-SRC (SRC), leading to trastuzumab resistance. Taken together, our findings establish that CDCP1 is a modulator of HER2 signaling and a biomarker for the stratification of breast cancer patients with poor prognosis. Our results also provide a rationale for therapeutic targeting of CDCP1 in HER2-positive breast cancer patients. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 18(4). DOI:10.1016/j.celrep.2015.03.044 · 8.36 Impact Factor
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    • "Recent data have shown that the initiation, development and homeostasis of most solid malignancies are not only related to tumor intrinsic features, but also to features related to the tumor microenvironment [7] [14] [23] [25] [83]. An increase of the stromal compartment within the cancer mass has been associated with worse disease outcome and increased cancer metastasis [34] [44] [47] [48]. "
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    • "Tumor growth relies not only on the malignancy of the tumor cells but also on the interaction between tumor cells and stromal cells1. Tumor stromal cells consist of various types of cells, including cells of the vascular and immune systems, fibroblasts, etc.2 The interactions between tumor cells and stromal cells occur in two ways: tumor cells can activate stromal cells in a paracrine fashion, and the activated stromal cells may have either tumor-promoting or tumor–suppressing functions. "
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    ABSTRACT: Endothelial cells (ECs) are critical for angiogenesis, and microRNA plays important roles in this process. In this study, we investigated the function and mechanism of miR-302c in the process of endothelial-mesenchymal transition (EndMT) in ECs. When miR-302c was overexpressed in HUVECs, the motility of the HUVECs was weakened; the expression levels of EndMT markers were also changed: vascular endothelial (VE)-cadherin was up-regulated, whereas β-catenin, FSP1, and α-SMA were down-regulated. Further in vivo and in vitro experiments showed that the growth of HCC was inhibited when co-cultured or co-injected with HUVECs overexpressing miR-302c. On the contrary, when miR-302c was suppressed in HUVECs, the opposite results were observed. Reporter assays showed that miR-302c inhibited metadherin (MTDH) expression through directly binding to its 3'UTR. In addition, compared to ECs isolated from normal liver tissues of HCC patients, ECs isolated from tumor tissues expressed markedly low levels of miR-302c but high levels of MTDH. These results suggest that EC-specific miR-302c suppresses tumor growth in HCC through MTDH-mediated inhibition of EndMT. MTDH and miR-302c might provide a new strategy for anti-angiogenic therapy in HCC.
    Scientific Reports 07/2014; 4:5524. DOI:10.1038/srep05524 · 5.58 Impact Factor
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